CS238941B1 - Method for purifying 2-mercapto-5-methyl-13,4-thiadiazole - Google Patents

Abstract

The solution relates to a method for purifying 2- -mercapto-5-methyl-1,3,4-thiadiazole of formula I N—N HjCAgJ-SH /X/' Compound of formula I is used as an intermediate in the production of the semi-synthetic antibiotic "Cefazolin", which has a broad spectrum of activity against Gram-negative and Gram-positive bacteria. The purity of the compound of formula I has a decisive influence on the quality of the final product and therefore increased attention must be paid to the purification operations. The method for purifying the compound of formula I consists in converting the crude /contaminated/ compound of formula I into a water-soluble salt - thiolate by reaction with a suitable inorganic or organic base in an aqueous medium at room temperature. The aqueous solution of the thiolate is purified with activated carbon, filtered and the purified compound of formula I is precipitated back after acidifying the solution with a strong mineral acid. During the entire purification operation, it is not necessary to increase the temperature of the reaction media, which has a positive effect on the quality and stability of the purified compound and further on the economy and technological complexity of the entire purification process.

Description

The present invention relates to a process for purifying 2-mercapto-5-methyl-1,3,4-thiadiazole of Formula I

N - N, _t h ₃ cX. _with J-sh ^{/ ιλ}

Said compound is used as an intermediate in the production of the semisynthetic cefazoline antibiotic, which has a broad spectrum of activity against both Gram-negative and Gram-positive bacteria.

Compound of Formula 1, prepared according to known synthetic procedures. Wennerbeck I .: Tautomeric cyclic thiones, Acta Chem. Scand. 20, 57, 196, Fujisawa Pharm. Co., Ger.

Offen 2, 162, 324 (1972) Fujisawa Pharm. Co .: Japan Kokai 72 32071, / 197¾¾ Eli Lilly and Co .: US Pat. 285872, (1972), analogous to the patent of ČSSR 168044, (197j) Fujisawa Pharm. Co .: Japan Kokai 72 07370, / 197¾¾ Merck Patent GmbH: Ger. Offen 2,652,127 (1977) Merck Patent GmbH: Ger. Offen 2,611,965,1773 Bollinger H., Zutter H .: Swiss. 596197, (1978) »Bollinger H., Mueller H. R., Swiss. 612191, (1979), is isolated from the reaction mixture in the crude state and must be purified before nucleophilic substitution with 7-aminocephalosporanoic acid derivatives.

Experience has shown that the purity of 2-mercapto-5-methyl-1,3,4-thiadiazole is one of the most important factors affecting the quality of the final product obtained. To date, the compound of formula X has been purified by crystallization from methanol, ethanol, from an oetone-water mixture, or purified by reprecipitation by precipitation by addition of water when dissolved in alcohol or acetone.

A disadvantage of these processes is the technological complexity associated with the fact that the compound of formula (I) is thermally labile in a saturated solution and crystallizes from the solution even with little cooling, resulting in clogging of pipes, fittings and filter.

Therefore, heated pipes, fittings and a heated pressure filter must be used to purify the compound of Formula I by crystallization. Another disadvantage of crystallization purification methods is the need for thermal stress on the compound of formula I, which results in contamination of the recrystallized product with thermal decomposition products.

A disadvantage of the purification processes, which are based on the precipitation of the purified product by the addition of water, is the necessity to use very large volumes of solvents. All these effects have a negative impact on the yield and cleaning efficiency and ultimately have a significant impact on the economy of the operation.

The process for purifying the compound of formula X according to the invention is based on converting a crude compound of formula I to a compound of formula II

Where M is an alkali metal or ammonium, respectively. substituted ammonium type R ¹ ', R ^2, R ³ HN ^+, wherein R ^1, R ^2, R ³ is hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C ₃ _ ₆ cycloalkyl, phenyl, benzyl, etc. by reacting the compound of formula I with the appropriate inorganic or organic base in an aqueous medium at a temperature of 0 to 30 ° C.

The compound of formula II, in the form of an aqueous solution, is purified by mixing with a suitable sorbent, filtered and converted back to the compound of formula I by acidifying the solution with a strong mineral acid.

The process according to the invention is carried out by dissolving 1 mol of the crude compound of the formula (I) in a solution obtained by dissolving 0.8 to 1.4 moles of sodium hydroxide and / or sodium hydroxide. potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, trimethylamine, diisopropylamine, dicyclohexylamine, dimethylbenzylamine, Ν, Ν-dimethylaniline, diethanolamine, triethanolaroin and the like (in 750 to 1 250 ml) used in 750 to 1 250 ml of base) or deionized water at 0 to 30 ° C.

The resulting aqueous solution containing the compound of formula (II) is purified by addition of a suitable sorbent such as bleaching earth, bentonite, silica gel and the like, preferably by adding 1 to 10% of the weight of the crude compound of formula I (depending on the impurity content). the solution was stirred for a further 15 minutes and then filtered.

The purified compound of formula I is precipitated from the filtrate after acidification with a strong mineral acid, e.g. hydrochloric acid to a pH 1,5 1.5 to 3.0, preferably to a pH = 2.0 to 2.1.

The precipitated compound of formula I is stirred at a temperature of 15-25 ° C for a further 1 hour, then separated by filtration or centrifugation, washed with distilled or deionized water until neutral and dried, preferably under vacuum.

The advantage of said cleaning process is that it is not necessary to raise the temperature throughout the cleaning operation, which has a positive effect on the stability and quality of the purified product. A further advantage is that the solution of the compound of formula (II) in water is stable, the purified product cannot be separated from the solution before acidification and thus the piping, filter, etc. cannot clog.

The invention is further described by way of example. These examples illustrate in some detail the purification possibilities of the crude compound of formula (I) without, however, limiting the scope of the invention in any way.

Example 1

132 g of crude 2-mercapto-5-methyl-1,3,4-thiadiazole are added to the solution obtained by dissolving 40 g of sodium hydroxide in 1000 ml of distilled water at 1.5 to 25 [deg.] C. and the solution is stirred at this temperature until into the ripple.

To the solution was added 7.0 g of activated carbon, stirred for a further 15 minutes, and then the solution was filtered. The filtrate is acidified, with vigorous stirring, at 15-25 ° C conc. hydrochloric acid to pH 2.0.

Indicative con. hydrochloric acid is about 100 ml. The acidified solution is stirred at this temperature for 1 hour, then the separated purified product is filtered off, washed with distilled water until neutral and dried to constant weight in vacuo.

117 g (88.6%) of purified 2-mercapto-5-methyl-1,3,4-thiadiazole are obtained in the form of white or slightly yellowish crystals, m.p. 182 DEG-184 DEG C. (dec.). The absorbance of a 4% solution of the purified substance in methanol at 400 nm in a 1 cm cuvette is at most 0.02 nm, with a titration content of at least 99%.

and

For C ₃ H ₄ N ₂ S ₂ / 132.21 g.mol ¹ / calculated! C, 27.25; H, 3.05; N, 21.19; S, 48.51 Found: C, 26.9; H, 3.1; S, 21.5; N, 48.4.

Example 2

To the solution obtained by dissolving 92.4 g of sodium bicarbonate in 1200 ml of deionized water at 15-25 ° C was added 132 g of crude 2-mercapto-5-methyl-1,3,4-thiazole diazole, and the solution was stirred at this temperature. temperature until clear.

Then 10 g of silica gel are added, the solution is stirred for a further 15 minutes and then filtered. The further procedure is identical to that of Example 1. 113 g (85.6%) of purified 2-mercapto-5-methyl-1,3,4-thiadiazole of melting point 183 DEG-184 DEG C. (with decomposition) are obtained. .

Absorbance and content are the same as Example 1.

For C ₃ H ₄ N ₂ S ₂ / 132.21 g.mol ^-1 / calculated: 27.25% C, 3.05 i H, 48.51% S, 21.19% N determined: 27.1% H, 48.4; S, 21.3

Example 3

132 g of crude 2-mercapto-5-methyl-1,3,4-thiadiazole are added to a solution formed by dissolving 101 g (139 ml) of triethylamine in 1200 ml of distilled water at 15-25 [deg.] C. and stirred at this temperature. temperature until clear.

10 g of bleaching earth are then added, the solution is stirred for a further 15 minutes and then filtered. The further procedure is the same as Example 1. 106 g (80.3%) of the purified product with a melting point of 182 DEG-184 DEG C. (decomposition) are obtained.

Absorbance and content are the same as Example 1.

For C ₃ H _S N ₂ S ₂ / gmol ^-1 132.21 / Calculated: 27.25% C, 3.05% H, 21.19% N, 48.51% S determined: 27.1% C, 3.2% H, N 21.4%, S 48.4%

Claims (5)

object of the invention A process for the purification of 2-mercapto-5-methyl-1,3,4-thiadiazole of the formula I ^Η 3 ^ε - 8 8 ^ 8 ^{Η / IZ} ', characterized in that the compound of the formula I is converted to the compound of the formula II N — N h ₃ cX. _with J | -SM ^{/ II / R} where M is alkali metal or ammonium, respectively. substituted ammonium type R ¹ R ² R ³ HN ^+, wherein R ^1, R ^2, R ³ is hydrogen, _χ 0 _ ₆ alkyl, C _1-6 hydroxyalkyl, C ₃ _ _g cycloalkyl, phenyl, benzyl, reacting a compound of formula Even with the appropriate inorganic or organic base in an aqueous medium, at a temperature of 0 to 30 ° C, the resulting solution is purified by mixing with a suitable sorbent and after filtration the purified compound of formula I is separated from the solution by acidification with a strong mineral acid to pH = 1.5 to 3 , 0. 2. The process according to claim 1, wherein the base is potassium hydroxide Sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, trimethylamine, triethylamine, diisopropyl amine, dicyclohexylamine, dimethylbenzylamine, N, N-dimethylaniline, diethanolamine, triethanolamine, preferably sodium hydroxide, and concentrated hydrochloric acid is used as the mineral acid. Process according to claim 1, characterized in that bleaching earth, bentonite, silica gel, preferably activated carbon in an amount of 1 to 10% of the weight of the crude compound of the formula I is used as the sorbent. 4. The process of claim 1 wherein the reaction is carried out at a temperature of 15-25 ° C. 5. The process of claim 1 wherein the pH of the solution after acidification is 2.0 to 2.1.